Genotypes and Comorbidities Associated with Trastuzumab-Induced Cardiotoxicity in HER2+ Breast Cancer

Since the introduction of trastuzumab (Herceptin) in the treatment landscape of HER2-positive breast cancer, studies have shown that the disease has begun to evolve in a manner that benefits patients, but the benefit is not without toxicities. Cardiotoxicity impacts a subset of patients with HER2-positive breast cancer who have received trastuzumab, and a recent study has found an association between trastuzumab-induced cardiotoxicity and HER2 Ile655Val A˃G polymorphism.

The single-institution study looked at genetic variants of HER2 Ile655Val A˃G, including AA compared with AG, and AA+GG compared with AG. Out of 655 patients, a large proportion of patients with the AA versus AG variants had cardiotoxicity (40% vs. 60%) compared with the number of patients without cardiotoxicity (66.7% vs. 33.3%), respectively. The overall risk (OR) among AA patients was 1.00 compared with 3.00 among AG patients (95% CI, 1.07-8.41; P = .037).

The comparison of the AA+GG group versus the AG group showed non-cardiotoxicity in 68.1% versus 31.9% of patients, respectively. Cardiotoxicity was observed in 40% of patients in the AA+GG group and 60% in the AG group. The difference in OR between the AA+GG patients and the AG patients was 1.00 versus 3.21 (95% CI, 1.15-8.96; P =.026).

As a method, investigators, led by Isabel Blancas, MD, were able to assess 66 patients who had a biochemical measurement of NT-proBNP during their trastuzumab treatment. The cardiovascular risk factors for the patients included diabetes, hypertension, smoking, hypercholesterolemia, and body mass index, with diabetes being the most relevant. At baseline the NT-proBNP above the range (OR, 5.9; 95% CI, 1.2-28.5; P =.028) and diabetes mellitus (OR, 22.0; 95% CI, 5.7-85.4, P =.000) were determined to be related to cardiotoxicity development.

Disease-free survival (DFS) and its correlation with polymorphisms were assessed in the study as well. This analysis showed that the hazard ratio (HR) for the comparisons of patients below the age of 50 and aged 50 years or older was 4.19 (P =.115). Patients who were menopausal compared with patients who were not had a HR of 0.13 (P =.030). Among those with anthracyclines versus those without, the HR was 1.38 (P =.579). Patients with stage II disease versus stage III disease showed a HR of 0.19 (P =.001). Finally, the AA genotype patients versus the AG genotype patients had a HR of 0.80 (P =.610).

In terms of overall survival (OS), the HR between patients below the age of 50 and aged 50 years or older was 0.005 (P =.031). Patients who were menopausal compared with patients who were not, had a HR of 7.8 (P =.296). Among those with anthracyclines versus those without, the HR was 5.0 (P =.254). Individuals with stage II HER2-positive breast cancer versus stage III disease showed a HR of 0.007 (P =.004). The AA genotype patients versus the AG genotype patients had a HR of 1.9 (P =.555).

Based on this analysis there was no association between HER2neu Ile655Val polymorphism and DFS or OS.

Overall, HER2 Ile655Val A˃G was designed to assess 93 patients using Taqman SNP technology. Cardiotoxicity is the study was characterized as a ≥ 10% decrease of the left ventricular ejection fraction (LVEF) from baseline, a LVEF below 40% or any clinical manifestation of heart insufficiency. Blancas et al also considered NT-proBNP cut-off points were to establish normal or abnormal values adjusted by patient age.

In consideration of the study’s conclusion, the investigators recommend a closer follow up for patients who are treated with trastuzumab. In addition, they recommend that physicians take preventative measures to establish glycemic control for patients treated with trastuzumab.

_Reference:

_{Blancas I, Gomez C, Martin-Perez FJ, et al. Predictor of trastuzumab-induced cardiotoxicity in breast cancer (BC) patients: HER2/neu 655 polymorphisms, biochemical and clinical features. J Clin Oncol. 2020: 38; (suppl; abstr 1033). doi: 10.1200/JCO.2020.38.15_suppl.1033}